Experimental Dysautonomia: Pathogenesis and Treatment

Summary

Principal Investigator: Steven A Vernino
Abstract: [unreadable] DESCRIPTION (provided by applicant): Patients with autoimmune autonomic neuropathy (AAN) classically have rapid onset of complete autonomic failure. Less severe forms of AAN occur frequently but are currently under recognized. To prove that AAN is an antibody-mediated disorder of neuronal synaptic transmission, we have developed a robust animal model, experimental autoimmune autonomic neuropathy (EAAN), by inducing autoimmunity against the neuronal ganglionic acetylcholine receptor in rabbits. The animal model develops predictably within two months and recapitulates the phenotype of the human disease. EAAN is the first disease-relevant chronic model of an antibody-mediated disorder of neuronal synaptic transmission. The objective of this project is to test the hypothesis that EAAN begins as a reversible autonomic ganglionopathy followed by a gradual, selective loss of postganglionic autonomic neurons. [unreadable] [unreadable] The specific aims are to 1) define the temporal pathophysiological profile of EAAN, 2) identify physiological features of EAAN that could be useful diagnostically in humans, and 3) evaluate hypothesis based treatment strategies through controlled treatment trials in the animal model. The first part of the project is a detailed physiological and pharmacological characterization of EAAN correlated with histological changes as they evolve over time. Quantitative pupillometry and telemetry recording of blood pressure and heart rate will be used to evaluate autonomic function and to pharmacologically dissect autonomic deficits. Histological studies of sympathetic and parasympathetic ganglia will include immunohistochemistry and electron microscopy to define the structure of the ganglionic synapse. The goal is an accurate definition of the pathophysiological evolution of this disorder and a correlation of physiology with histopathology. These translational studies will provide insight into disease mechanisms, identify characteristic features to improve clinical diagnosis, and provide rationale for new treatment strategies. In the final year of the project, controlled therapeutic trials that would be impractical in patients will be performed in EAAN rabbits. [unreadable] [unreadable] In additional to its clinical significance, this project is relevant to understanding ganglionic synaptic transmission, neurological autoimmunity, pathophysiology of acquired dysautonomia, the recuperative and adaptive capabilities of ganglionic transmission and the vulnerability of neurons to autoimmune attack. [unreadable] [unreadable]
Funding Period: 2004-02-01 - 2008-01-31
more information: NIH RePORT

Top Publications

  1. ncbi Autoimmune and paraneoplastic channelopathies
    Steven Vernino
    Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9036, USA
    Neurotherapeutics 4:305-14. 2007
  2. pmc Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current
    Z Wang
    Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9036, USA
    Neurology 68:1917-21. 2007
  3. pmc Dysfunction of the pupillary light reflex in experimental autoimmune autonomic ganglionopathy
    Shalini Mukherjee
    Department of Neurology UT Southwestern Medical Center 5323 Harry Hines Blvd, Dallas, Texas 75390 9036, USA
    Auton Neurosci 137:19-26. 2007
  4. pmc Invited Article: Autonomic ganglia: target and novel therapeutic tool
    Steven Vernino
    Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA
    Neurology 70:1926-32. 2008
  5. pmc Characterization of ganglionic acetylcholine receptor autoantibodies
    Steven Vernino
    Department of Neurology, UT Southwestern Medical Center, Dallas Texas 75390 9036, United States
    J Neuroimmunol 197:63-9. 2008
  6. ncbi Neuronal acetylcholine receptor autoimmunity
    Steven Vernino
    Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9036, USA
    Ann N Y Acad Sci 1132:124-8. 2008
  7. pmc Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy
    Steven Vernino
    Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9036, USA
    Auton Neurosci 146:3-7. 2009

Scientific Experts

  • Steven A Vernino
  • Shalini Mukherjee
  • Z Wang
  • P Sandroni
  • P A Low
  • C H Gibbons
  • J Jordan
  • C Schroeder
  • R Freeman

Detail Information

Publications8

  1. ncbi Autoimmune and paraneoplastic channelopathies
    Steven Vernino
    Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9036, USA
    Neurotherapeutics 4:305-14. 2007
    ..These disabling neurological disorders may be dramatically responsive to immunomodulatory therapy. Future studies will likely lead to identification of other ion channel antibodies and other autoimmune channelopathies...
  2. pmc Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current
    Z Wang
    Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9036, USA
    Neurology 68:1917-21. 2007
    ..Previous clinical studies and observations in animal models suggest that AAG is an antibody-mediated neurologic disorder...
  3. pmc Dysfunction of the pupillary light reflex in experimental autoimmune autonomic ganglionopathy
    Shalini Mukherjee
    Department of Neurology UT Southwestern Medical Center 5323 Harry Hines Blvd, Dallas, Texas 75390 9036, USA
    Auton Neurosci 137:19-26. 2007
    ..These characteristic abnormalities of the pupillary light reflex may prove to have diagnostic value...
  4. pmc Invited Article: Autonomic ganglia: target and novel therapeutic tool
    Steven Vernino
    Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA
    Neurology 70:1926-32. 2008
    ..Recent evidence also suggests a potential role for acetylcholinesterase inhibitors in the treatment of postural tachycardia syndrome...
  5. pmc Characterization of ganglionic acetylcholine receptor autoantibodies
    Steven Vernino
    Department of Neurology, UT Southwestern Medical Center, Dallas Texas 75390 9036, United States
    J Neuroimmunol 197:63-9. 2008
    ..Muscle and ganglionic AChR antibody specificities are distinct. Antibody crossreactivity between AChRs with different alpha subunits is uncommon but can occur...
  6. ncbi Neuronal acetylcholine receptor autoimmunity
    Steven Vernino
    Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9036, USA
    Ann N Y Acad Sci 1132:124-8. 2008
    ..For example, antibodies against alpha7-type AChRs have been identified in a few patients with encephalitis. It is still unclear if antibodies against receptors in the central nervous system can directly cause disease...
  7. pmc Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy
    Steven Vernino
    Department of Neurology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9036, USA
    Auton Neurosci 146:3-7. 2009
    ....